Compositions and methods of making a photoactive agent

Abstract

An improved two stage reaction process for production of mono-L-aspartyl chlorin e 6 . In a first stage, the activation reaction between chlorin e 6 and a carbodiimide produces a previously unknown anhydride in an activation reaction product (Formula I). This reaction product is purified to remove a significant proportion of the precursors of di-L-aspartyl chlorin e 6 . The purified activation reaction product contains a higher concentration of the previously unknown anhydride. This purified reaction product is used in a second stage: a coupling reaction of the purified activation reaction product with aspartate. The coupling reaction produces a coupling reaction product that has significantly reduced di-L-aspartyl chlorin e6 concentration. This reduced di-L-aspartyl chlorin e6 concentration facilitates purification of mono-L-aspartyl chlorin e6 from the coupling reaction mixture.

What is claimed is: 
     
       1. A process for preparing mono-L-aspartyl chlorin e 6 , or a pharmaceutically acceptable salt thereof, comprising:
 combining chlorin e 6  with a carboxyl activating agent to obtain a mixture comprising a Formula I intermediate 
 
       
         
           
           
               
               
           
         
       
       or a salt thereof;
 isolating the Formula I intermediate, or salt thereof; and 
 combining the isolated Formula I intermediate, or salt thereof, with an amine-containing reagent, to form talaporfin sodium, or a pharmaceutically acceptable salt thereof. 
 
     
     
       2. The process of  claim 1 , wherein combining the chlorin e 6  with the carboxyl activating agent comprises reacting the chlorin e 6  with a carbodiimide. 
     
     
       3. The process of  claim 2  wherein the carbodiimide is N,N′-dicyclohexyl-carbodiimide, N-ethyl-N′-(3-dimethylaminopropyl) carbodiimide hydrochloride, or mixtures thereof. 
     
     
       4. The process of  claim 1 , wherein combining the chlorin e 6  with the carboxyl activating agent comprises reacting the chlorin e 6  with a carbodiimide in the presence of dimethyl sulfoxide or dimethyl formamide. 
     
     
       5. The process of  claim 1  wherein reacting the chlorin e 6  with the carboxyl activating agent comprises reacting the chlorin e 6  with N-ethyl-N′-(3-dimethylaminopropyl) carbodiimide hydrochloride or N,N′-dicyclohexyl-carbodiimide. 
     
     
       6. The process of  claim 1  wherein isolating the Formula I intermediate, or salt thereof, comprises separating the Formula I intermediate, or salt thereof, from the mixture by using activated silica to yield a substantially pure Formula I intermediate, or salt thereof. 
     
     
       7. The process of  claim 1  wherein combining the isolated Formula I intermediate, or salt thereof, with an amine-containing reagent, comprises reacting the isolated Formula I intermediate, or salt thereof, with sodium aspartate to form talaporfin sodium. 
     
     
       8. The process of  claim 1  wherein combining the isolated Formula I intermediate, or salt thereof, with an amine-containing reagent, comprises combining the isolated Formula I intermediate, or salt thereof, in the presence of dimethyl sulfoxide, with L-aspartic acid or ester thereof to form talaporfin sodium. 
     
     
       9. The process of  claim 1  wherein combining the isolated Formula I intermediate, or salt thereof, with an amine-containing reagent, comprises coupling the isolated Formula I intermediate with L-aspartic acid or ester thereof in an aqueous alkaline solution to form a tetra-sodium salt of mono-L-aspartyl chlorin e 6 .